Interstitial cystitis (IC) is a chronic inflammatory disease of the urinary bladder, affecting mainly women. The etiology and pathogenesis of the disease are obscure. A chronic submucosal inflammation has been found, especially in those patients with small bladder capacities or pyuria. During inflammation, the activation of sensory C fibers not only initiates reflex micturition and mediates pain sensation but also stimulates but also stimulates the local release of neuropeptides such as substance P (SP) and neurokinin A (NKA). We found that SP triggers histamine release in guinea pig bladder. Other investigators have shown that together with histamine, it promotes vasodilation and plasma extravasation. The mast cells and inflammatory mediators in the bladder wall during the initial stages of IC deserve attention. Inflammatory cell activity is far more important than the actual number of inflammatory cells found in a bladder biopsy specimen relative to the pathogenesis of IC. We have developed an actively sensitized guinea pig model to study the release of inflammatory mediators in bladder. Antigen (ovalbumin) induced histamine, prostaglandin, and leukotriene (LT) release from isolated bladder tissue from sensitized animals. In vivo exposure of sensitized female guinea pigs to ovalbumin (via urethral catheterization) induced a prompt and marked increase in micturition frequency and decreased both the pressure and volume at which micturition occurs. Ovalbumin significantly increased the permeability of the bladder mucosa to 14C-urea in sensitized animals. We propose to : 1) determine if the antigen applied intravesically induces neurogenic inflammation and if the pretreatment of the animals with capsaicin or SP antagonist decreases the antigen-induced plasma extravasation; 2) examine bladder tissue from control and sensitized guinea pigs for the presence of subgroups of mast cells, distribution of neuronal elements, tissue concentrations of LTs, histamine, and SP; 3) determine the effects of SP and NKA on bladder function and histamine release; 4) study factors, such as epithelium denudation, that intensify the activity of these peptides; 5) study factors that decrease the release of peptides or inhibit their effect on bladder function and mast cell release. The correlation of our functional studies with the morphological and biochemical studies of Drs. Keith, Brownfield, and Graziano should provide important new information on the mechanisms by which inflammatory disease affects bladder function.